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Systematic biases in DNA copy number originate from isolation procedures.

ABSTRACT: BACKGROUND:The ability to accurately detect DNA copy number variation in both a sensitive and quantitative manner is important in many research areas. However, genome-wide DNA copy number analyses are complicated by variations in detection signal. RESULTS:While GC content has been used to correct for this, here we show that coverage biases are tissue-specific and independent of the detection method as demonstrated by next-generation sequencing and array CGH. Moreover, we show that DNA isolation stringency affects the degree of equimolar coverage and that the observed biases coincide with chromatin characteristics like gene expression, genomic isochores, and replication timing. CONCLUSION:These results indicate that chromatin organization is a main determinant for differential DNA retrieval. These findings are highly relevant for germline and somatic DNA copy number variation analyses.

SUBMITTER: van Heesch S

PROVIDER: S-EPMC4054094 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Systematic biases in DNA copy number originate from isolation procedures.

van Heesch Sebastiaan S Mokry Michal M Boskova Veronika V Junker Wade W Mehon Rajdeep R Toonen Pim P de Bruijn Ewart E Shull James D JD Aitman Timothy J TJ Cuppen Edwin E Guryev Victor V

Genome biology 20130424 4

<h4>Background</h4>The ability to accurately detect DNA copy number variation in both a sensitive and quantitative manner is important in many research areas. However, genome-wide DNA copy number analyses are complicated by variations in detection signal.<h4>Results</h4>While GC content has been used to correct for this, here we show that coverage biases are tissue-specific and independent of the detection method as demonstrated by next-generation sequencing and array CGH. Moreover, we show that ...[more]

PMID: 23618369

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Project description:BACKGROUND: Some diseases, like tumors, can be related to chromosomal aberrations, leading to changes of DNA copy number. The copy number of an aberrant genome can be represented as a piecewise constant function, since it can exhibit regions of deletions or gains. Instead, in a healthy cell the copy number is two because we inherit one copy of each chromosome from each our parents. Bayesian Piecewise Constant Regression (BPCR) is a Bayesian regression method for data that are noisy observations of a piecewise constant function. The method estimates the unknown segment number, the endpoints of the segments and the value of the segment levels of the underlying piecewise constant function. The Bayesian Regression Curve (BRC) estimates the same data with a smoothing curve. However, in the original formulation, some estimators failed to properly determine the corresponding parameters. For example, the boundary estimator did not take into account the dependency among the boundaries and succeeded in estimating more than one breakpoint at the same position, losing segments. RESULTS: We derived an improved version of the BPCR (called mBPCR) and BRC, changing the segment number estimator and the boundary estimator to enhance the fitting procedure. We also proposed an alternative estimator of the variance of the segment levels, which is useful in case of data with high noise. Using artificial data, we compared the original and the modified version of BPCR and BRC with other regression methods, showing that our improved version of BPCR generally outperformed all the others. Similar results were also observed on real data. CONCLUSION: We propose an improved method for DNA copy number estimation, mBPCR, which performed very well compared to previously published algorithms. In particular, mBPCR was more powerful in the detection of the true position of the breakpoints and of small aberrations in very noisy data. Hence, from a biological point of view, our method can be very useful, for example, to find targets of genomic aberrations in clinical cancer samples.

Dataset Information

Systematic biases in DNA copy number originate from isolation procedures.

Publications

Systematic biases in DNA copy number originate from isolation procedures.

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